The present invention relates to thienopyranecarboxamide derivatives, to pharmaceutical compositions containing them and to uses for such derivatives and compositions.
U.S. Pat. No. 5,403,842, Leonardi et al., and its continuations in part (U.S. Pat. Nos. 5,474,994 and 5,605,896) claim heterobicyclic derivatives bearing substituted phenylpiperazines as basic moieties linked to the heterocyclic ring by a variety of spacer groups. Among said derivatives, compound A (Ex. 11) is of relevant interest due its very high uroselective activity. 
Compound A is endowed with good affinity for the xcex11A adrenoceptor and is able to selectively inhibit contractility of the prostatic urethra in a dog model without substantial effects on blood pressure (Leonardi et al., J. Pharmacol. Exp. Therap., 281:1272-1283, 1997.)
7-Oxo-7H-thieno[3,2-b]pyran-3-carboxylic acid and its N,xcfx89-aminoalkylamides are compounds not yet reported in the literature. The present invention is directed to the new structural class of the N-(substituted phenyl)-Nxe2x80x2-[xcfx89-(5-substituted-7-oxo-7H-thieno[3,2-b]pyran-3-carbonylamino)alkyl]piperazines.
Compounds of this class are endowed with enhanced selectivity toward the xcex11 adrenergic receptor, in particular with respect to the 5-HT1A receptor, and improved in vivo uroselectivity even compared to compound A, with remarkable effects on relaxation of prostatic urethra and very low activity in lowering blood pressure. This activity profile suggests the safer use of the compounds of the invention in the therapy of obstructive syndromes of the lower urinary tract, including benign prostatic hyperplasia (BPH), without side-effects associated with hypotensive activity.
In one aspect, the invention is directed to compounds of Formula I: 
wherein
R is an aryl, cycloalkyl or polyhaloalkyl group,
R1 is chosen from the group consisting of alkyl, alkoxy, polyfluoroalkoxy, hydroxy and trifluoromethanesulfonyloxy; each of R2 and R3 independently is chosen from the group consisting of a hydrogen, halogen, alkoxy and polyfluoroalkoxy group, and n is 0, 1 or 2.
The preferred aryl group which R may represent without limitation is phenyl. The preferred cycloalkyl group that R may represent without limitation is cyclohexyl. The preferred polyhaloalkyl group that R may represent without limitation is trifluoromethyl. The preferred alkyl group which R1 may represent without limitation is C1-4 lower alkyl. Preferred alkoxy groups (C1-4) which R1, R2, and R3 may represent without limitation are lower alkoxy groups, most preferably methoxy. Preferred polyfluoroalkoxy which R1, R2, and R3 may represent without limitation are trifluoromethoxy or 2,2,2-trifluoroethoxy.
The preferred value for n is 1.
The invention further provides pharmaceutical compositions comprising a compound of Formula I or a N-oxide or pharmaceutically acceptable salt of such a compound in admixture with a pharmaceutically acceptable diluent or carrier.
In another aspect, the present invention is directed to methods for selectively preventing contractions (including noradrenaline-mediated contractions) of the urethra and lower urinary tract, without substantially affecting blood pressure, by administering one or more selected compounds of Formula I to a mammal (including a human) in need of such treatment in an amount or amounts effective for the particular use.
In yet another aspect, the invention is directed to methods for blocking xcex11 receptors, by delivering to the environment of said receptors, e.g., to the extracellular medium, (or by administering to a mammal possessing said receptors) an effective amount of a compound of the invention, in this way relieving diseases associated to overactivity of said receptors.
The very high uroselectivity of the compounds of this invention has been tested in the dog model described in Example 10, where their efficacy in antagonizing the contractions of prostatic urethra in the presence of very limited effects on blood pressure has been shown, in comparison to compound A and to another well-known xcex11-antagonist, prazosin.
Accordingly, it is a primary object of the present invention to provide a method of treating BPH which avoids any undue side effects due to acute hypotension (i.e., limited effects on blood pressure).
It is another object of the present invention to provide pharmaceutical compositions comprising 7-oxo-7H-thieno[3,2-b] pyran compounds which are selective xcex11 adrenoceptor antagonists, which compositions are effective for the treatment of BPH optionally including a carrier or diluent.
It is another object of the present invention to provide a method of treating BPH using 7-oxo-7H-thieno[3,2-b] pyran compounds which are selective xcex11 adrenoceptor antagonists.
Another aspect of the invention is the use of new compounds for lowering intraocular pressure, and the treatment of cardiac arrhythmia and erectile dysfunction.
Other features and advantages of the present invention will be apparent to those skilled in the art from the following detailed description and claims.
All patents, patent applications and literature references cited in this application are incorporated by reference in their entirety.
The adrenergic antagonistic activity of the compounds of the invention renders them useful as agents acting on body tissues particularly rich in xcex11-adrenergic receptors (such as prostate and urethra). Accordingly, the anti-adrenergic compounds within the invention, established as such on the basis of their receptor binding profile, can be useful therapeutic agents for the treatment, for example, of micturition problems associated with obstructive disorders of the lower urinary tract, including but not limited to benign prostatic hypertrophy (BPH).
BPH is a progressive condition, which is characterised by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urinary stream and hesitancy or delay in starting urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of a prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the ageing male population. BPH is observed in approximately 70% of males over the age of 70. Currently, the worldwide stated method of choice for treating BPH is surgery. A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery.
xcex1-Adrenergic receptors (McGrath et al., Med. Res. Rev., 9:407-533, 1989) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many xcex1-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin, terazosin, alfuzosin, doxazosin, tamsulosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma). xcex1-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter noradrenaline, and antagonists (phenoxybenzamine and prazosin, terazosin, alfuzosin, doxazosin, tamsulosin are antagonists), which act to block the effects of noradenaline. Many of these drugs are effective, but also produce unwanted side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
The above reported agonists are selective for the xcex12 adrenergic receptor whereas most antagonists are selective for the xcex11 adrenoceptor, with the exception of tamsulosin which shows a relevant affinity also for the 5-HT1A receptor. Many of the cited xcex11 antagonists are currently used for the therapy of BPH but, due to their poor uroselectivity, they are liable to cause side effects of cardiovascular type.
Recent pharmacological, biochemical and radioligand-binding studies evidenced three different xcex11-receptor subtypes with a high affinity for prazosin, namely xcex11A-(xcex11A-), xcex11B-(xcex11b-) and xcex11D-(xcex11d-), with lower case subscripts being used for recombinant receptors and upper case subscripts for receptors in native tissues (Hieble et al., Pharmacol. Rev., 47:267-270, 1995). In functional studies xcex11-receptors with a low affinity for prazosin have also been identified and termed xcex11L-receptors (Flavahan and Vanhoutte, Trends Pharmacol. Sci., 7:347-349, 1986; Muramatsu et al., Pharmacol. Comm., 6:23-28, 1995).
Several studies have demonstrated the presence of these xcex11-adrenergic receptor subtypes in the lower-urinary-tract tissues as reviewed by (Andersson, K. E., xe2x80x9c4th International Consultation in Benign Prostatic Hyperplasia (BPH)xe2x80x9d, Paris, Jul. 2-5, 1997, pages 601-609).
Several studies have shown that the human prostate receives innervation from both the sympathetic and parasympathetic nervous systems.
The adrenergic nerves are considered responsible for prostatic smooth-muscle tone by releasing noradrenaline, stimulating contraction-mediating xcex1-adrenoceptors. Approximately 50% of the total urethral pressure in BPH patients may be due to xcex1-adrenoceptor-mediated muscle tone. Functional studies have indicated the occurrence of important adrenoceptor functions in prostatic adenomatous and capsular tissue. Clinical studies with the prototypical adrenoceptor-selective antagonist, prazosin, reinforced the key role of xcex11 adrenoceptors in the control of prostatic smooth-muscle tone. This was also confirmed in the laboratory by studies showing that, although both xcex11- and xcex12- adrenoceptors can be identified within the human prostate, contractile properties are mediated primarily by xcex11 adrenoceptors. Many clinical investigations have confirmed that xcex11-adrenoceptor blockade relieves lower urinary tract symptoms (LUTS), both of irritative and obstructive type, in patients with BPH.
Two distinct xcex11- adrenoceptor subtypes have been suggested to be present in the human prostate, one with high (xcex11H) and one with low (xcex11L) affinity for prazosin. All three high-affinity xcex11 adrenoceptor subtypes found in molecular cloning studies have been identified in prostatic stromal tissue. The xcex11a subtype was found to be the dominant, representing about 60-85% of the xcex11-adrenoceptor population. Recent findings suggest that there may be differences in subtype populations between normal and hyperplastic prostates, the ratios between the subtypes xcex11a:xcex11b:xcex11d being 85:1:14 in BPH and 63:6:31 in non-BPH tissue.
The xcex11A-adrenoceptor was reported to mediate the contractile response of the human prostate in vitro. Ford et al. found that the xcex11A adrenoceptor may not mediate contractile responses to noradrenaline, and suggested as a candidate the xcex11L adrenoceptor. Findings by Kenny et al. (Br. J. Pharmacol., 118:871-878, 1996) support the view that the xcex11L adrenoceptor, which appears to share many of the characteristics of an xcex11A adrenoceptor, mediates the contractile response of the human prostate.
On the other hand, it has also been suggested that the xcex11A and xcex11L adrenoceptors may represent distinct pharmacological forms of the same receptor.
The affinity of the compounds of the invention for each receptor can be assessed by receptor binding assays, for example as follows:
(1) xcex11-adrenergic-receptor subtypes: using the specific ligand 3H-prazosin, according to Testa et al., Pharmacol. Comm. 6: 79-86, 1995; Cotecchia, S., Schwinn, D. A., Randall, R. R. and Lefkowitz, F. J., Proc. Natl. Acad. Sci. USA, 85: 7159-7163 (1988); Furchgott. R.E., Handbook of Experimental Pharmacologyxe2x80x94New Series, 283-335 (1972); Michel, M. C., Hanft, G. and Gross, G., Brit. J. Pharmacol. 111: 533-538 (1994); Schwinn, D. A., Lomasney, J. W., Lorenz, W., Szklut, P. J., Fremcau, R. T., Yang-Feng, T. L., Caron, M. G., Lefkowitz, R. J. and Cotecchia, S., J Biol. Chem. 265: 8183-8189 (1990); Testa, R., Guarneri, L., Ibba, M., Strada, G., Poggesi, E., Taddei, C., Simonazzi, I. and Leonardi, A. Europ. J. Pharmacol. 249: 307-315 (1993).
(2) 5HT1A-serotonergic receptor: using the specific ligand 3H-8-OH-DPAT according to Fargin et al., Nature 335: 358-360, (1988); Kobilka, B. K. et al., Nature 329: 75-79 (1987); Cullen, B. R., Meth. Enzym. 152: 684-704 (1987); Gozlan, H. et al., J. Receptor Res. 7: 195-221 (1987).
The xcex11L-adrenergic receptor is not yet cloned and, therefore, the functional affinity of the compounds of the invention for this subtype can be assessed by using an isolated organ preparation as reported by Testa et al., J. Pharmacol. Exp. Ther. 281: 1284-1293, (1997); Oshita, M., Kigoshi, S. and Muramatsu, I., Br. J. Pharmacol. 108: 1071-1076 (1993).
In vitro testing of the compounds of this invention on the above receptors is described in Examples 8 and 9 below.
The drugs having xcex11-adrenergic antagonistic activity currently used for the symptomatic therapy of BPH are poorly subtype selective and subject to cause relevant side effects due to their hypotensive activity.
Thus there is a need for selective xcex11-antagonists which do not subject the BPH patient to the side effects, especially the cardiovascular side effects of said treatment.
The high uroselectivity of the compounds of the invention has been demonstrated by the dog model of the Example 10 below, where their efficacy in counteracting the contractions of prostatic urethra at doses that do not influence blood pressure has been shown.
The compounds according to the invention may be generally prepared as follows: 
Direct condensation of 7-oxo-7H-thieno[3,2-b]pyran-3-carboxylic acids of the formula I with the xcfx89-aminoalkylamino derivatives 2 (SCHEME 1) leads to the compounds of the invention. The condensation can be carried out in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide or diethyl cyanophosphonate) optionally in the presence of a promoting agent (e.g., N-hydroxysuccinimide, 4-dimethylaminopyridine or N,Nxe2x80x2-carbonyldiimidazole) in an aprotic or chlorinated solvent (e.g., N,N-dimethylformamide or chloroform) at xe2x88x9210/140xc2x0 C. (Albertson, Org. React., 12:205-218, 1962; Doherty et al., J. Med. Chem., 35:2-14, 1992; Ishihara, Chem. Pharm. Bull., 39:3236-3243, 1991). In some cases the activated ester or amide intermediates (such as O-(N-succinimidyl) esters or acyl imidazolides) can be isolated and further reacted with 2 to be transformed into the corresponding amides (I) in an aprotic or chlorinated solvent at 10/100xc2x0 C. This kind of condensation is well illustrated in the Examples. Another activated intermediate which can be used is the mixed anhydride of 1, obtainable reacting 1 with an alkyl chloroformate in the presence of a tertiary amine (e.g., triethylamine or N-methylmorpholine), which is reacted with 2 at 0-80xc2x0 C.; optionally a promoting agent (e.g., 1-hydroxypiperidine) may be added before the amine addition (Albertson, Org. React., 12:157, 1962).
Alternatively the condensation can be carried out without a solvent at 150-220xc2x0 C. (Mitchell et al., J. Am. Chem. Soc., 53; 1879, 1931) or in high-boiling ethereal solvents (e.g., diglyme).
The condensation can also be performed through preparation and optional isolation of reactive derivatives of 1 such as acyl halides. Formation of acyl halides of compounds of formula 1 and reactions with amines 2 to form amides is well documented in the literature and known to people skilled in the art.
Also less reactive derivatives of 1 can be used, such as alkyl esters, which in turn can be converted into I in the presence of a condensing agent (e.g., trimethylaluminum) in an aprotic and/or chlorinated solvent (e.g., hexane, dichloromethane) at xe2x88x9210/80xc2x0 C., or without solvents at 80-180xc2x0 C., (Weinreb et al., Tetrahedron Lett., 4171, 1977; Lipton et al., Org. Synth., 59:49, 1979).
By the same methods of condensation reported above and using H2NCH2(CH2)nCH2X (with X=halogen or OH) as a reagent, 1 can be transformed into 3. In the case of X=OH, the alcoholic group is then converted into a suitable leaving group by methods well known to those skilled in the art. Compounds 3 (with X=leaving group such as halogen or alky/arylsulphonyloxy group) can be subsequently reacted with an appropriate phenylpiperazine 8 bearing the desired phenyl group. The nucleophilic substitution is carried out preferably, but not necessarily, at a temperature within the range of 20-200xc2x0 C. in a polar solvent such as dimethylformamide, acetonitrile, methanol, or without any solvent, usually in the presence of a base such as potassium carbonate. See also Gibson""s chapter in Patai: xe2x80x9cThe Chemistry of the Amino Groupxe2x80x9d, p. 45 et seq., Wiley International Science, N.Y., 1968.
The preparation of compounds 2 which are not commercially available is disclosed in the literature and is well known to those skilled in the art, and is usually carried out performing nucleophilic substitution of a phenylpiperazine 8 on a N-(xcfx89-haloalkyl)phthalimide or a proper xcfx89-haloalkylnitrile or haloalkylamide by the method illustrated above for the condensation of compounds 3 and 8, or by addition of an xcex1, xcex2-unsaturated alkylnitrile or alkylamide in a proper solvent (e.g., acetonitrile, dimethylformamide, a chlorinated solvent or other aprotic polar solvent) at a temperature between 0xc2x0 C. and the reflux temperature of the solvent. Standard phthalimido-group deprotection or reduction of the amido or cyano group then provides compounds 2, and can be performed by methods well known to those skilled in the art.
The acids 1 of the invention in which R represents cycloalkyl or aryl group can be synthesized (SCHEME 2) starting from methyl 2-acetyl-3-hydroxythiophene-4-carboxylate (prepared as described in J. Chem. Soc. Perkin Trans I, 507, 1986), which can be esterified with the proper alkanoyl or aroyl chloride by using methods very well known to those skilled in the art. Alternative procedures include the same methods described above for the amidification of 1, which could be applied as well in the esterification step to afford 4. 
Monobromination of the methylketo group of 4 can afford 5, which can then be reacted with triphenylphosphine (typically by reflux in acetonitrile, toluene, or other aprotic solvent), to give the phosphonium salt 6. A subsequent intramolecular ester-Wittig reaction applied to this substrate yields the thieno[3,2-b]pyranes, 7.
Hydrolysis of the ester group of compounds 7 is accomplished by acid or base catalysed procedures that are well known to those skilled in the art, yielding compounds 1.
Such hydrolysis procedures include the use of sodium hydroxide in aqueous ethanol at 40-75xc2x0 C., or lithium hydroxide in aqueous dimethylformamide, or tetrahydrofuran at 40-100xc2x0 C.
The compounds 1 where R is a polyfluoroalkyl group can be prepared from 2-acetyl-3-hydroxythiophene-4-carboxylate following the cyclization procedure described by Riva et al., (Synthesis, 195-201, 1997) by direct cyclization in the presence of anhydrous polyfluoroalkanoyl anhydrides catalysed by 1,8-diazabicycloundec-7-ene.
The compounds I where R1 is a trifluoromethanesulphonyloxy group can be synthesized starting from compounds I where R1 is a hydroxy group using procedures well known to those skilled in the art, by way of example without limitation, using trifluoromethanesulphonic anhydride or N-phenyltrifluoromethanesulphonimide in aprotic solvents such as 1,2-dichloroethane or other chlorinated solvents or toluene, at a temperature in the range between 20xc2x0 C. and the temperature of reflux of the solvent (Hendickson et al., Tetrahedron Letters, 4607-4510, 1973). The N-oxides of the compounds I may be synthesized by simple oxidation procedures known to those skilled in the art. The oxidation procedure described in P. Brougham in Synthesis, 1015-1017 (1987) allows differentiation of the two nitrogen atoms of the piperazine ring and both the N-oxides and N,Nxe2x80x2-dioxides to be obtained.
Preparation of the phenylpiperazines 8, which has not been described in the literature, is well documented in the examples and uses synthetic procedures well known to those skilled in the art, which comprise the synthesis of the proper aniline through standard reactions and the subsequent cyclization with bis-(2-chloroethyl)amine to afford the piperazine following the method of Prelog (Collect. Czech.Chem.Comm., 5:497-502, 1933) or its variations (Elworthy, J. Med. Chem., 40:2674-2687, 1997).